Concrete evidence of cognitive dysfunction in ME

[62milestogojoe]

The neuro-inflammation, might cause mitochondrial dysfunction, from the oxidative stress it causes. I have read that dysfunctional mitochondria, because of the increase in oxidative stress they create.

Can cause a positive feedback loop, to some degree, keeping the neuro-inflammation in place, with excessive oxidative stress.

So it seems like it might be necessary to slow or stop the source of the neuro-inflammation and decrease the oxidative stress also, from the dysfuctional mito. that might be helping to perpetuate the neuro-inflammation/oxidative stress/mitochondrial dysfunction cycle.

Just a couple of thoughts!

Jim

Hi and thanks-if inflammation runs on a positive feedback loop than I think IL-6 and TNF-alpha may be implicated putting the brain under greater oxidative stress.

There has been evidence that in states of sleep deprivation (that's us, with disruption of N3 [-the former stage 4] sleep Il-6 increases which may contribute to that positive feedback. I am scratching my head!

 

[62milestogojoe]

I would like to see these results replicated first before I would make much of them.

Its just that the sample was very small (9 CFS cases), and there do not appear to be any corrections applied for multiple comparisons. (When you do lots of comparisons, this raises your likelihood of getting something significant just by chance alone. Here they say they have done an ROI analysis - which means you're not required to do such stringent corrections as you would with a whole brain analysis, but they don't say what their regions of interest are, why they chose them, and why they didn't at least apply some corrections).

The correlations look impressive, but I would also like to know how many correlational analyses they performed that didn't come out significant. If its more than, say, 20, then these ones might just look good due to chance.

Until we see a good replication - preferably with a bigger sample - we can't tell whether these effects are genuine or not.

Hi, I agree. One swallow does not make a summer.

 

[62milestogojoe]

Lowering infection pressure did stop the BSE epidemic but there are still sporatic cases. Same happened with KURU. Kuru and BSE are different strains.

Hi, I fetched my clinical virology texts down and given the rider that it is from the mid nineties it has been found that prion disease 'elicits no antibody, inflammation or interferon response to infection'.
Maybe we could contrast that with-
'The extent and duration of neurologically damaging events by pathogen - immune interaction has been broadly examined in HIV infection of the brain.(21) There is inflammatory cytokine deregulation of normal brain immune inhibitory systems which causes neuronal death and damage. Astrocyte death, reactivation of microglial cells and astrocytes, dendritic simplification, dymelination and virus re-seeding can also occur(22).'

I think this is a different model to a spongiform model.

 

[lansbergen]

Hi, I fetched my clinical virology texts down and given the rider that it is from the mid nineties it has been found that prion disease 'elicits no antibody, inflammation or interferon response to infection'.

That WAS the consensus.

Now they have many different antibodies produced in labanimals.

For inflamation: https://www.ncbi.nlm.nih.gov/pubmed/27046083
Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.

And Aguzzi Microglia in prion diseases.

There are more

 

[62milestogojoe]

That WAS the consensus.

Now they have many different antibodies produced in labanimals.

For inflamation: https://www.ncbi.nlm.nih.gov/pubmed/27046083
Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.

And Aguzzi Microglia in prion diseases.

There are more

Thanks lansbergen do you have the energy to pursue that regarding neuroinflammatory processes vis a vis the model in the diagrams I posted.

I worked in the lab last Monday and Wednesday (aluminium assay for dialysis patients and copper, zinc, seleniums for ITU patients), spent the whole of Thursday, Friday and Saturday morning working on the Osaka paper and am starting to get 'crash' warnings.

Any help from PR members would be much appreciated.

 

[lansbergen]

and am starting to get 'crash' warnings.

You must rest.

 

[62milestogojoe]

Thanks,I will

 

[GlassHouse]

I definitely have brain inflammation. Just last month I had my appointment with Dr Peterson to review the results of my spinal tap, which showed high protein (tap was clean with no blood so the results are very accurate). High protein means breakdown of the blood brain barrier due to inflammation (might be infection, autoimmune, or both causing it).

I've also had several QEEGs that showed progressive traumatic brain injury (comparing scans every 6 months).

I can sleep up to 22 hrs without an alarm but my brain waves while I'm awake are delta waves (the slowest waves that are usually only seen in the deepest stage of sleep). It feels like I haven't slept in 6 years.

I've had 6 sleep studies that show my night time sleep looks normal but then during the daytime studies (multiple sleep latency tests) my results are the same as someone who hadn't slept in 2-3 days. So I'm extremely tired/ cognitively impaired. (I also have fatigue/ PEM as measured by a 2-day CPET. I view the tiredness and fatigue as different symptoms).

I'm part of the atypical ME/CFS subset and my blood tests show increased inflammation as my illness goes on (systemic inflammation).

While my illness was gradual and progressive, I feel very strongly that it started with a strange high fever (103-104F) that didn't break for 6 days. None of my doctors back then did any tests, except for STDs (because that's all they ever wanted to test for when I was in college). Not that I have pent-up rage about this ....

 

[Jesse2233]

Tagging @Jonathan Edwards on behalf of @62milestogojoe as he is not yet able to tag

 

[62milestogojoe]

I would like to see these results replicated first before I would make much of them.

Its just that the sample was very small (9 CFS cases), and there do not appear to be any corrections applied for multiple comparisons. (When you do lots of comparisons, this raises your likelihood of getting something significant just by chance alone. Here they say they have done an ROI analysis - which means you're not required to do such stringent corrections as you would with a whole brain analysis, but they don't say what their regions of interest are, why they chose them, and why they didn't at least apply some corrections).

The correlations look impressive, but I would also like to know how many correlational analyses they performed that didn't come out significant. If its more than, say, 20, then these ones might just look good due to chance.

Until we see a good replication - preferably with a bigger sample - we can't tell whether these effects are genuine or not.

Hi Woolie, the issue then is perhaps how do we 'encourage' health providers/ research institutions to begin the process....which at the end of the day is what the post is about.

If findings are confirmed then health authorities have no escape in that they must confront the reality of suffering of hundreds of thousands of people and make an attempt to alleviate the suffering with more than a nice chat.

 

[ljimbo423]

the issue then is perhaps how do we 'encourage' health providers/ research institutions to begin the process....which at the end of the day is what the post is about.

I don't know if this has been mentioned in this thread but Dr. Jarod Younger is heavily involved in researching neuro-inflammation in cfs. The more researchers involved the better though. Here is a link to a transcript, with many links to different parts of the interview, that Jarod Younger did with Joe Cohen of selfhacked.com. LINK

Jim

 

[Woolie]

Hi Woolie, the issue then is perhaps how do we 'encourage' health providers/ research institutions to begin the process....which at the end of the day is what the post is about.

If findings are confirmed then health authorities have no escape in that they must confront the reality of suffering of hundreds of thousands of people and make an attempt to alleviate the suffering with more than a nice chat.

I did have a quick look at papers that cited the paper you mention, to see if any had tried to replicate this one. There were 90+ citations. Amongst these, I couldn't find any that had attempted a replication, but I have to admit I skimmed a lot of the titles. You could see what you can find?

A lot of the brain stuff being done in MECFS is highly descriptive, open to multiple interpretations and doesn't really narrow down the pool of potential explanations. An even bigger problem with neuroimaging studies specifically is that they are hugely prone to false positives. This is why you can so easily find studies claiming that a 6-week course in mindfulness will increase your grey matter volume! (this is achieved by performing thousands of comparisons and only focusing on those that yield a result in the expected direction).

But I do think this stuff on inflammation is interesting, and it would be good to see someone pursue this question systematically, and report ALL their results, clearly setting our their predictions and method and assumptions.

But we also have to face the very real possibility that this line of enquiry was not pursued because it was not fruitful (the findings were not secure, could not be replicated). When the researchers themselves don't pursue it further, you've got to ask yourself why.

I'll eat my words if you find me a study that has successfully replicated it!

 

[62milestogojoe]

I did have a quick look at papers that cited the paper you mention, to see if any had tried to replicate this one. There were 90+ citations. Amongst these, I couldn't find any that had attempted a replication, but I have to admit I skimmed a lot of the titles. You could see what you can find?

A lot of the brain stuff being done in MECFS is highly descriptive, open to multiple interpretations and doesn't really narrow down the pool of potential explanations. An even bigger problem with neuroimaging studies specifically is that they are hugely prone to false positives. This is why you can so easily find studies claiming that a 6-week course in mindfulness will increase your grey matter volume! (this is achieved by performing thousands of comparisons and only focusing on those that yield a result in the expected direction).

But I do think this stuff on inflammation is interesting, and it would be good to see someone pursue this question systematically, and report ALL their results, clearly setting our their predictions and method and assumptions.

But we also have to face the very real possibility that this line of enquiry was not pursued because it was not fruitful (the findings were not secure, could not be replicated). When the researchers themselves don't pursue it further, you've got to ask yourself why.

I'll eat my words if you find me a study that has successfully replicated it!

Hi Woolie, did you have a good look at the panel showing the side by side scans of ME vs non ME patients? Unless the controls were youthful teenagers and the ME patients in their 60s then I think the results look fairly unequivocal with regard to degree of inflammation. To get 9 false positives and 10 false negatives would be like winning the lottery- 1 in 14,000,000 chance. Don't think so.

Astrocytes are one of the 'tagged' targets in this PET scan-the major immune cell in the brain and they look pretty active in ME patients! Clearly they had better access to imaging results than we will and with accuracy of PET scan technique to a resolution of 1mm they seemed very sure of functional location.

Using mindfulness as an analogy to PET scan is facile. It's like comparing a Yorkshire terrier with a Blue whale.

Having said that, we need to see replication of the method.

 

[Woolie]

Hi Woolie, did you have a good look at the panel showing the side by side scans of ME vs non ME patients? Unless the controls were youthful teenagers and the ME patients in their 60s then I think the results look fairly unequivocal with regard to degree of inflammation. To get 9 false positives and 10 false negatives would be like winning the lottery- 1 in 14,000,000 chance. Don't think so.

Figure 1 is a bit misleading because it shows one "representative case" from each group (read: the one that looked the best). The different images are different slices through the brain, not different people, alas.

Figure 2 is the one where all the action happens. That's the straight up voxelwise analysis. It shows that some voxels in the areas of interest were associated with higher 11C-(R)-PK11195 uptake in the CFS/ME group than in the control group.

To be fair on the researchers, and to correct my earlier post, it does appear that in Figure 2, they have only plotted voxels that remained significant after performing a modest correction for multiple comparisons (using p = .005). Sorry for saying earlier that they hadn't. The Figure shows that for this small group, there was a significantly higher uptake in some voxels in the patient group.

I don't know much about the 11C-(R)-PK11195 marker they used, but I'm also wondering how its uptake is affected by mental activity and blood flow. There are going to be differences between patients and controls here. It would seem you would need to do some sort of baseline resting state oxygen uptake PET scan to compare it to (this would have to be on a different day). I suppose its not easy to do that with PET, because giving people stuff with radioactive tags is not great for them.

 

[62milestogojoe]

Figure 1 is a bit misleading because it shows one "representative case" from each group (read: the one that looked the best). The different images are different slices through the brain, not different people, alas.

Figure 2 is the one where all the action happens. That's the straight up voxelwise analysis. It shows that some voxels in the areas of interest were associated with higher 11C-(R)-PK11195 uptake in the CFS/ME group than in the control group.

To be fair on the researchers, and to correct my earlier post, it does appear that in Figure 2, they have only plotted voxels that remained significant after performing a modest correction for multiple comparisons (using p = .005). Sorry for saying earlier that they hadn't. The Figure shows that for this small group, there was a significantly higher uptake in some voxels in the patient group.

I don't know much about the 11C-(R)-PK11195 marker they used, but I'm also wondering how its uptake is affected by mental activity and blood flow. There are going to be differences between patients and controls here. It would seem you would need to do some sort of baseline resting state oxygen uptake PET scan to compare it to (this would have to be on a different day). I suppose its not easy to do that with PET, because giving people stuff with radioactive tags is not great for them.

Hi Woolie, I'm just back from a day at the coalface doing TPNs for ITU patients by ICP-MS. I'm a bit jaded and will get back to you when I can re-read the paper and try to be coherent. I appreciate the time you've taken in reading the paper thoroughly.
The paper is being read by a med micro consultant, a biochemistry consultant and a chief immunology biomedical scientist at the mo and hopefully they will be able to give some input into to the discussion too. Thanks

 

[Hip]

It might be interesting to look at the ME/CFS brain autopsies, and where they found enteroviral infection in the brain.

 

[62milestogojoe]

Figure 1 is a bit misleading because it shows one "representative case" from each group (read: the one that looked the best). The different images are different slices through the brain, not different people, alas.

Figure 2 is the one where all the action happens. That's the straight up voxelwise analysis. It shows that some voxels in the areas of interest were associated with higher 11C-(R)-PK11195 uptake in the CFS/ME group than in the control group.

To be fair on the researchers, and to correct my earlier post, it does appear that in Figure 2, they have only plotted voxels that remained significant after performing a modest correction for multiple comparisons (using p = .005). Sorry for saying earlier that they hadn't. The Figure shows that for this small group, there was a significantly higher uptake in some voxels in the patient group.

I don't know much about the 11C-(R)-PK11195 marker they used, but I'm also wondering how its uptake is affected by mental activity and blood flow. There are going to be differences between patients and controls here. It would seem you would need to do some sort of baseline resting state oxygen uptake PET scan to compare it to (this would have to be on a different day). I suppose its not easy to do that with PET, because giving people stuff with radioactive tags is not great for them.

It is worth highlighting a couple of issues I think in defense of the research

• General criteria for inclusion of ME/CFS patients was very strict to rule out false positives
• Age criteria for patients and controls was very strict to rule out false positives (age related inflammation)
• Th 18-KDa translocator protein used as a biomarker is highly specific since TSPO functions as a modulator of immune cell oxidative bursts
• TSPO is therefore an appropriate tool to assess neuroinflammation in disease of the brain
• Dynamic data was collected over one hour of scanning of the patients' brains and the 23 frames were correlated using internationally accepted (MNI) protocols
• If we look at the P values (given that this is a small representative group) there is robust evidence not only of neuroinflammation but correlation to significant ME symptomatology-
• As an example, take the cytokine data regarding correlation between left thalamic intralaminar nucleus and disruption in sleep/wake cycles. P =0.00028!

advocate role in science is vital for the generation of robust and pertinent statistically significant results. I think this is a strong piece of work by the Japanese.

I cannot answer why it has not been repeated, but neither can you so your doubts are I believe speculation. As an aside it was a Japanese who found this protocol in Japanese which is perhaps why it hadn't come to the surface before.

There are some promising results here, why don't we push for the necessary repeat of the work?

I'm not in work until next week. I look forward to hearing what brighter health professionals than me have to say in the biomed unit.

 

[Woolie]

I cannot answer why it has not been repeated, but neither can you so your doubts are I believe speculation.

I spent quite some time reading and evaluating this study for you, because I thought you genuinely wanted to discuss the work and might value some expert input (I'm a University academic and an active researcher in cognitive neuroscience). But your statement above was unnecessarily aggressive, and suggests you're not interested in active discussion, but only in having your beliefs confirmed. So I won't comment again.

If there is any part of you still interested in careful critical analysis of science then read this thread:
http://forums.phoenixrising.me/inde...d-as-well-as-psych-studies.53513/#post-890168

 

[62milestogojoe]

I spent quite some time reading and evaluating this study for you, because I thought you genuinely wanted to discuss the work and might value some expert input (I'm a University academic and an active researcher in cognitive neuroscience). But your statement above was unnecessarily aggressive, and suggests you're not interested in active discussion, but only in having your beliefs confirmed. So I won't comment again.

If there is any part of you still interested in careful critical analysis of science then read this thread:
http://forums.phoenixrising.me/inde...d-as-well-as-psych-studies.53513/#post-890168

I'm so sorry you feel that way. Please reconsider.

 

[Woolie]

I'm so sorry you feel that way. Please reconsider.

Okay, no worries. Its easy to get impassioned when its our own disease. I've guilty of the same thing myself. If you have any new questions about the study or about what I posted, tag me and I'll respond.